Disease Progression Model of Pancreatic Cancer
Developed by Penn Researchers

(Philadelphia, PA) - Building on previous work, researchers at the University
of Pennsylvania School of Medicine have developed an animal model
of pancreatic cancer that closely mimics disease progression in humans.
From this, they hope to develop new treatments for this deadly disease.
Advanced pancreatic cancer is among the most lethal of cancers, with a
one-year survival rate after chemotherapy of only 17 to 28 percent of
patients, according to the National Cancer Institute.

Sunil R. Hingorani, MD, PhD, and David A. Tuveson,
MD, PhD, both in the Departments of Medicine and Cancer Biology,
and colleagues, engineered mice to express two mutant genes commonly associated
with pancreatic cancer: Kras, an oncogene, and p53,
a well-studied tumor suppressor. The investigators linked physiological,
cellular, and genomic changes due to mutations in Kras and p53
in the mice to changes similar to that observed in pancreatic cancer patients.
They report their findings in the May issue of Cancer Cell.

Clinical symptoms in the mutant mice mirrored those displayed in pancreatic
cancer patients, such as abdominal swelling and muscle loss. Similarly,
the progression of pancreatic cancer metastases paralleled that seen in
the human disease. “In this model, pancreatic cancer metastasizes
to the liver, lungs, diaphragm, and adrenal glands, all the same places
that human pancreatic cancer metastasizes,” says Tuveson.

The frequency of metastases to these various organ sites was also highly
similar to that seen in humans. In human patients, 60 to 80 percent develop
metastases to the liver; and 50 to 60 percent develop metastases to the
lungs. In the genetically modified animals, 63 percent displayed liver
metastases, and 45 percent displayed lung metastases-further emphasizing
the accuracy of this model in mimicking human pancreatic cancer.

To understand the progression of pancreatic cancer, Hingorani and colleagues
studied cell lines derived from primary tumor and metastasized cells.
From this, the researchers established the occurrence of genomic instability
in the mouse model. Genomic instability-continuous formation of mutated
chromosomes-leads to widespread genetic changes throughout the affected
cells. Genomic instability is seen in many human epithelial cancers, including
pancreatic cancer, and is thought to be a driving force in the transition
from local tumor growth to metastases of cancers. According to Hingorani,
“This model may prove useful to understanding human pancreatic and
other epithelial cancers because the key event of genomic instability
that has been very difficult to model in the mouse appears to be recapitulated
here.”

In the pancreatic tumors and metastases from the mouse model, the investigators
characterized other molecules implicated in pancreatic cancer. Often,
the expression of molecules such as growth factors and their receptors
will offer possible targets for treatment. The researchers were surprised
to discover a high degree of heterogeneity in expression among these key
molecules across the specimens. After ruling out the likelihood that this
variability resulted from additional acquired mutations in known key tumor
suppressor pathways, Hingorani suggests, “there may actually be
unique genetic routes to pancreatic cancer, such that not all pancreatic
cancers are equivalent.”

The development of the first animal model for pancreatic cancer that fully
imitates the progression of the human condition will likely open many
new doors in understanding this debilitating disease. “With a model
that can generate the full spectrum of disease, from preinvasive to invasive
and metastastic lesions, we can begin to tease out the events that are
linked to the progression of pancreatic cancer,” explains Hingorani.
“In trying to understand what events are required to create and
support invasive and metastatic disease, we hope to translate our findings
into better therapies,” states Hingorani.

The study was funded in part by the National Institutes of Health, the
National Cancer Institute, the National Pancreas Foundation, and an AACR-PanCAN
Career Development Award. Study co-authors are Lifu Wang, Chelsea Combs,
Therese B. Deramaudt, and Anil K. Rustgi from Penn, as well as Asha S.
Multani and Sandy Chang, from M.D. Anderson Cancer Center, and Ralph H.
Hruban from Johns Hopkins University.

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was established in 1973 as a center of excellence in cancer research,
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